Effective therapy for diabetes generally involves a combination of two types of exogenous insulin formulations due to fluctuations in the demand for insulin. A fast-acting meal time insulin formulation is used to dispose of meal-related blood glucose surge, and a sustained release formulation is employed to regulate the constant hepatic glucose output and maintain a basal insulin level. The sustained release formulation is typically injected several times a day at regular intervals. Unfortunately, many diabetics are unwilling to comply with this therapy due to the discomfort and inconvenience of multiple injections. Therefore, sustained release insulin formulations suitable for non-injection routes are desired.
Recently, delivery of therapeutics through pulmonary routes has proven to be advantageous for certain drugs. This approach eliminates the need for needles, limits irritation to the skin and body mucosa (common side effects of transdermally, iontophoretically, and intranasally delivered drugs), and eliminates the need for nasal and skin penetration enhancers (typical components of intranasal and transdermal systems that often cause skin irritations/dermatitis). Pulmonary administration is also economically attractive, amenable to patient self-administration, and is often preferred by patients over other alternative modes of administration.
Insulin is an ideal candidate for pulmonary delivery due to its relatively small molecular weight (about 5,800 daltons). However, the preparation of sustained release formulations for delivery to the lung is very challenging. In order to reach the alveoli in the deep lung, where absorption of drugs takes place, a drug is ideally delivered in relatively small particles, which tend not to deposit prematurely in the mouth, throat or upper airway. Furthermore, the drug should be delivered in a composition that releases its active ingredient in a sustained manner. Since small particles collectively contain a higher surface area than large particles of the same total mass, small particles release their ingredients faster than large particles. Therefore, the challenge in the preparation of sustained release pulmonary compositions is how to include an appropriate control mechanism in the small particles to slow down release of the drug.
A number of methods have been employed to control the release rate of drugs from pulmonary pharmaceutical compositions (see, e.g., Zeng et al., 1995). Examples of these methods include the use of liposomes or biodegradable microspheres, and modification of the drug so that the active form of the drug is not readily released. Another method is to include the drug in an insoluble complex. For example, the injectable sustained release insulin formulations often contain insulin in a crystallized form, which releases insulin more slowly than compositions comprising free insulin. The insulin crystals that exhibit a satisfactory sustained release profile in injectable compositions, however, are not suitable for pulmonary delivery, because the crystals are too big and deposit prematurely before they reach the deep lung.
Crystallization procedures that result in microcrystals have also been attempted to manufacture small crystals of insulin that can be delivered to the lung, but these procedures are complicated and tedious (WO 01/00674). Simple and effective methods of preparing sustained release compositions for pulmonary delivery are thus still desirable.